2, 4b-dimethyl-1-acetaldehydo-2-(beta-ketopropyl)-1, 2, 3, 4, 4a, 4b, 5, 6, 7, 9, 10, 10a- dodecahydrophenanthrene-4, 7-dione and methods of preparing the same



Ab-D M Y 1 ACETALDEHYDQ- -Ifl-KETQF DROP N HR D WD DNE ND M THF DDS @F PREPARMG THE SANIE Lewis H. Sarett, Princeton, N-J,-, Geerge :l:,Pu os,; Philadelphia, Pa, and William F. Johns, MortonGrove, lllhgassignorsto Merck & Co Inca, Rahway, N.J., a corporation of New lersey No Drawing. Uriginal application september 9,1953; Serial No, 379,282, new Patent No.- 2,837,516, dated June 3,. 1958. Divided and thisapplication-March ,4', l957,1Serial.No. 643,886 r 2 Claims. (Cl. 260-3409) This application is a division of Serial No. 379,282, filed September 9, 1953, now Patent No, 2,837,516.v

This invention relates to novel dodecahydrophenanthrene compounds, and processes of preparing the same. More particularly, it is concerned with a method of form; ing the membered D ring of the-steroid molecule from an appropriately substituteddodecahydrophenanthrene compound, and with the new compounds so obtained; Specifically, it is concerned with a novel method of-converting 2,4b-dimethyl-1-(B-hydroXyethyD -2-methallyl 7- ethylenedioxy l,2,3,4,4a,4b,'5,6,7,8,10,-10a dodecahydrophenanthrene-4-ol to 2,4b-dimethyl-7-ethylenedioxyv2-(5 ketopropyl) l-acetaldehydo-1,2,3,4,4a,4b,5,6,7,8,10,10a: dodecahydrophenanthrene-4-one, and the'process of converting this compound to A -3-ethylenedioxy pregna diene-11,20-dione, and the valuable, compoundsso prepared.

The preparation of valuable steroid substances by total synthesis, involving formation ofthe four. ringsyst'em, introduction of angular methyl groups, at positionsLlO and 1'3, andplacing ofdesiredfunctio'nal substituents inrthe ring system, presents a formidable challenge. In addition tothese ditficulties, the problem'is further complicated by the stereochemistry of'steroidalisubstances. Thus, saturated steroids, with a minimum of six asymmetric centers, are capable. of existing in at least=sixty-fot1r stere'olch'emical modifications. Inspite of these difliculties efforts have been made to prepare steroids by. total synthesis in view of the importance and value of steroids such as cortisone, and the; scarcity of raw materialssuite ableas starting materials for the preparation oithesedm; p.ortant:products.

It is an-object of thepresentinvention; to provide a methndn p ep ring-StcrOi 1. mp ndSj om od c hydrophenanthrjene, compounds; Another, objectv is to :pro: vide a process for'the'preparation-of-ll ketoprogesterone, from functionally substituted: dodecahydrophenanthrene compounds. I

An additional objectis to providenovel dodecahydro phenanthrene compounds which are useful L as intermediates in the synthesis of ll-keto. progesterone, p

, Other objects willbe apparentfrorn thedetailed-de scription of this invention hereinafter provided.

Inaccordance with the; present; invention; it is now found, that derivatives of 2,4h-dirnethyl-1-(,B-hydroxy ethyl): 2 methallyl-1,Z,3,4,4a,4b,5,6,7,9,10,\l0a dodecahydrophenanthrene-4-ol-7-o ne wherein the 7-keto. sub stit uent is blockedor. protected by a substituent conyertible, to, keto by hydrolysis, can be converted into ited rates Patent? 9 ice 2.1:, M -3,11,20 triketo-pregnadieneby a novelsequence of chemical reactions shown" in the following flowsheet:

wherein Rirepresents a: substituent: convertible towa keto groupby. acid hydrolysis, and R represents a keto or a hydroxyl r group,

In this sequence of'reactions the starting, material; Compound'I, is first treated withanoxidizing agentrto produce the. l aeetaldehyde-491mmcompound, Compound II. T hiscompound iszthemreacted:withosmium tetroxide and'tl're resulting-osmate ester. hydrolyzedzto convertgthe methall-yl; substituent', at position 2-; to ,a fi,ry dihydr0Xyis0-, bIutyl; substituent, thereby, producing; Compound III: Upon-reacting Compound IILwitlr periodic acid-the:fi ,rydihydroxyisobutyl;substituent is converted'to; an p,l :eto-v Pr ps group t pr du esGomponndrve acbs e of: Gomp un lv o; orm he-fi membe d D ng f the steroid molecule is effective by reacting this compound W han kalitqproduce p noun p n y rc y ing Compound V with acid, the ethylenedioxy groupfis cleaved forming a keto gjroup atp osition 3 .and causing; the double bond to shift-fromthe 5,6-position; to the'4,5,- p osition thereby, producing Compound VI.

Alternatively, as indicated in thefi'owsheetabove, Com: pound IV can be prepared directlyfrom Corinpound II. In this method Compound His reacted with ozoneand the resulting ozojriide, reduced to' obtain Compound IM wherein R represents a hydrocarbon radical or hydrogen, X represents oxygen or sulfur, and n represents the integer or 1, are most suitable for use as starting materials in our process. Examples of such compounds having a cyclic ketal, mercaptol or hemithioketal group that might be mentionedare 2,4b dimethyl 1 (fl-hydroxyethyD-Z methallyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 ol, 2,4b-dimethyl-1-(;8-hydroxyethyl) 2 methallyl 7 ethylenemercaptol 1,2, 3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene-4-ol, and 2,4b-dimethyl 1 (,B-hydroxyethyl) 2 methallyl-7- ethylenehemithioketal 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol, or the corresponding 4,7- dione compounds. The 2,4b-dimethyl-l-(fi-hydroxyethyD- 2-methallyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol can be prepared as described in the copending application of two of us, Serial No. 310,134, filed September 17, 1952, now Patent No. 2,786,064. The 2,4b-dimethyl-1-(fl-hydroxyethyl)-2-methallyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrenei-one can be prepared by subject ing 2,4b-dimethyl 1 (2-tosyloxyethyl)-2-methallyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene (prepared as described in copending application Serial No. 310,134, now Patent No. 2,786,064) to alkaline hydrolysis. The 2,4b-dimethy1- 1 S hydroxy ethyl) 2 methallyl 7 ethylenemercaptol 1,2,3,4,4a, 4b,5,6,7,8,l0,l0a dodecahydrophenanthrene 4 ol and 2,4b dimethyl 1 (B hydroxyethyl) 2 methallyl 7- ethylenehemithioketal 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol can be obtained by reacting 2,4b dimethyl 1 ()3 hydroxyethyl) 2 methallyl- 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4- ol-7-one (prepared as described in copending application Serial No. 310,134, now Patent No. 2,786,064) with ethanedithiol and B-mercaptoethanol respectively in the presence of fused zinc chloride and anhydrous sodium sulfate. Similarly, the corresponding 4-one compounds can be prepared utilizing the 4,7-dione as the starting material. Although, as indicated above, various substituents can be used to block or protect the 7-keto group, we have found that the cyclic ketal derivatives, and in particular the 7-ethylenedioxy derivative, are most conveniently utilized as the starting material in the processes of our invention.

The ethylenedioxy group of the intermediate products formed in our process, namely, Compounds II, HI, and IV, is cleaved by hydrolysis with acid, for example by heating with perchloric acid, to produce the corresponding 7-keto compounds. In this hydrolysis, the double bond at the 8a:9 position is shifted to the 818a position, thus forming an cap-unsaturated ketone.

For the purpose of providing a better understanding of this invention, our processes can be exemplified by the application to a specific starting material, the ethylenedioxy derivative of 2,4b-dimethyl-2-methallyl-1-(,B-hydroxyethyl) 1,2,3,4,4a,4b,5,6,7,9,10,102. dodecahydro phenanthrene-4-ol-7-one.

In the first step of our process, this starting material, 2,4b dimethyl 7 ethylenedioxy 2 methallyl l (,8- hydroxyethyl) 1,2,3,4,4a,4b,5,6,7,8,10,l0a-dodecahydrophenanthrene-4-ol is reacted with an oxidizing agent to convert the 4-hydroxy substituent to a keto group and to convert the fi-hydroxyethyl to the acetaldehydo substituent. We have found that this oxidation is most conveniently accomplished by reacting a solution of the starting material in an organic base with a complex formed by reacting an organic base with chromium trioxide, for example the pyridine-chromium trioxide complex. This method of oxidizing primary and secondary alcohols to the corresponding carbonyl compounds is described in the copending application of one of us, Serial No. 292,985, filed June 11, 1952. Thus, this oxidation is readily effected by intimately contacting a solution of the starting com pound in pyridine with the complex formed by reacting chromium trioxide with pyridine and allowing the reaction mixture to stand at room temperature for sufficient time to complete the oxidation. The 2,4b-dimethyl-7-ethylenedioxy 2 methallyl 1 acetaldehydo 1,2,3,4,4a,4b, 5,6,7,8,10,l0a dodecahydrophenanthrene 4 one is recovered by diluting the reaction mixture with water, extracting the aqueous solution with a water immiscible solvent for the product, such as ethyl ether, chromatographing the resulting ether solution over acid-washed alumina, and eluting the product with a mixture of petroleum ether and ethyl ether.

Although the principal product of the oxidation reaction is 2,4b dimethyl 7 ethylenedioxy 2 methallyl lacetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one, small amounts of other oxidation products such as 2,4b-dimethyl-7-ethylenedioxy-Z-methallyl 1 3 hydroxyethyl) 1,2,3,4,4a,4b,5,6,7,8,10,1021- dodecahydrophenanthrene-4-one and the corresponding 1-(carboxymethyl) compound are also obtained. These products can be reduced by reaction with lithium aluminum hydride to produce an epimeric form of the starting material. This epimeric form of the starting material can be used in the present process as effectively as the orig inal starting compound, thereby increasing the final yield of product.

In the next steps of our process, the 2-methallyl substituent of 2,4b dimethyl 7 ethylenedioxy 2 -methallyl 1 acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one is converted to a p-ketopropyl group. As indicated on the flow sheet shown above, this can be accomplished by either direct oxidation, or by cleavage of the intermediate glycol (Compound III).

In carrying out this conversion by the direct oxidation, the 2,4b-dimethyl-7-ethylenedioxy-2-methallyl-l-acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one is dissolved in a suitable solvent, such as a lower aliphatic alcohol, the solution cooled to a low temperature of about C., and ozonized oxygen containing one equivalent of ozone based on the dodecahydrophenanthrene is passed through the solution. The resulting reaction mixture is warmed to about 0 C. and the ozonide. decomposed in accordance with methods known in the art, as for example, by reduction with a small amount of zinc and aqueous acetic acid. After decomposition of the ozonide, the product 2,4b-dimethyl- 7-ethylenedioxy-2(B-ketopropyl)-l-acetaldehydo 1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one is readily recovered by concentrating the reaction mixture under diminished pressure, extracting the concentrate with ether, chromatographing the concentrate over acid washed alumina, eluting with a mixture of petroleum ether-ethyl ether, and evaporating the resulting eluate.

Alternatively, and in accordance with a preferred emaeaaooo bodiment of our invention, the fi-ketopropyl compound, is obtained by a. twostepprocess involving. treating the methallyl compound with osmium tetroxide and decomposing the resulting osmate. ester to produce the corresponding 2- (B -dihydroxyisobutyl) compound, and 5 cleaving this latter product by treatment with periodic acid. In this procedure, the 2,4b-dirnethyl-7-ethylenedioxy 2 methallyl-l-acetaldehydo-l,2,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene-4-one is reacted with osmium tetroxide to form the corresponding osmate ester, the reaction being preferably effected in a suitable inert solvent medium such as benzene, ethyl ether, tetrahydrofuran, and the like, or in a mixture of such solvents. The reaction is completed by allowing the reaction mixture to stand at room temperature for about one hour. The osmate ester is then decomposed by adding ethanoland treating the resulting solution with an aqueous solution of sodium su'lfite. The glycol formed in this reaction mixture can be recovered by filtering the resulting reaction mixture, concentrating this solution under diminished pressure, extracting this concentrate with chloroform, and evaporating the chloroform extract.

The 2,4b-dimethyl-7-ethylenedioxy-2-( @y-dihydroxyisobutyl) -1-acetaldehydo-1,2,3 ,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one is then conveniently converted to the corresponding Z-(fl-ketopropyl) compound by reacting a solution of this product ina mixture of tetrahydrofuran and pyridine'with a solution of periodic acid and allowing the resulting reaction mixture to stand at about room temperature for about one-halfhour. At this point, the mixture is diluted with water and the tetrahydrofuran removed by concentration under diminished pressure. The resulting concentrate is then extracted with benzene and the 2,4b-dirnethyl-7-ethylenedioxy-2-(fl-ketopropyl)- 1-acetaldehydo-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one obtained by concentration of the henzene extracts.

The Z-(B-ketopropyl) compound is then reacted with an alkaline reagent to efiect ring closure and form the corresponding steroid compound. Thus, on heating a suspension of 2,4b-dimethyl 7 ethylenedioxy-Z-(fl-ketopropyl) 1 acetaldehydo-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in an aqueous solution of potassium hydroxide at about 100 C. for nineteen hours A 8-ethylenedioxy-pregnadiene-11,20-dione is formed. This product is readily recovered from the resulting alkaline solution by extraction with a suitable water immiscible solvent for the product such as chloroform, and concentration of the resulting solvent extracts.

The 3-ethylenedioxy compound so obtained is hydrolyzed by heating with acids to produce A -pregnadiene- 3,11,20-trione.

The derivatives of A -pregnadiene-3,11,20 trione, wherein the 3-keto group is protected by a group convertible to keto by hydrolysis with acid, obtained in accordance with the present invention are valuble compounds useful as intermediates in the synthesis of cortisone. Thus, for example, dl-A -3-ethylenedioxy-pregnadiene-11,20-dione can be selectively hydrogenated by reaction with hydrogen in the presence of Raney nickel catalyst to produce dl-A -3-ethylcnedioxy-pregnene-11,20- dione by the method shown in Berichte, 72, 182 for reducing A -3-hydroxy-20-keto pregnadiene to A -3-hydroxy- 20-keto-pregnene. The d1-A -3-ethylenedioxy-pregnene- 11,20-dione can then be converted to cortisone by the methods described in the Journal of the American Chemical Society 74, 4974 (1952).

The 2,4b-dimethy1 1 (pl-hydroxyethyl)-2methallyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol used as the starting material in the examples illustrating the processes of this invention, can be prepared as described in copending application, Serial No. 310,134, filed September 17, 1952, now Patent 2,786,- 064.

EXAMBLEI 2,4b dimethyl-Zethylenedioxy-2 methrtllyl-l-qcetaldehy do 1,2,3,4,4,4b,5;6,7,8,10,1(2a dodecahydrqp hennn thrert-4-0ne i To the complexfrom 380 mg. of chromium trioxide dissolved in 3.5. cc. 'otv pyridine was. added 384 mg. of 2,4b dimethyl-7 ethylenedioxy-Z-methallyl-1-( fl-hydroxyethyl) 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol in.3 cc. ofpyridine, After standing overnight at room temperature, the reaction mixture was diluted withwater and extracted withether. The combined ether extracts werewashed with wa'ter, dried and concentrated. The resulting crude crystalline product was chromatographed on 12 g. of acidawa shed alumina, With petroleum. ether-ether there wascluted first 2,4b-dimethyl-7- ethylenedioxy-Z-methallyl-lracetaldehydo 1,2,3,4,4a,4b,5, 6,7,23,10,10aadodecahydrophenanthrene-4-one melting at 1484159 C. after recrystallization from ether followed y b e h hylen diox -2-m h y (I -1 droxyethylj 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one, M.P. 182-6f C. from ether. Further elution with methanol gave 2,4b-dirnethyl-7-ethylenedioxy-Z-methallyl 1 carboxymethyl 1,2,3,4,4a,4,b,5,6,7, 8,10,10a-dodecahydrophenanthrenew4-one melting at 215- 216 C. after purification by recrystallization from ethyl acetate.

The above, l-(B-hydroxyethyl) compound and the l- (carboxymethyl) compound mayfbe reduced with lithium aluminum hydride in tetrahydrofuran to produce the C-11 epirner of 2,4b-dimethyl-7-ethylenedioxy-Z-methallyl 1 (B hydroxyethyl) 1,2,3,4,4a,4b,5,6,7,8,10,10a k dodeca hydrophenanthrene-4-ol, the original starting material.

' The 2,4b-dimethy1- 7-ethylenedioxy-Z-methallyl l-acetaldehyde-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahYdrophenanthrene 4-one on acid hydrolysis yields 2,4b-dimethyl-2- methallyl- 1 acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenef l,7-dione.

Similarly, on acid hydrolysis 2,4b-dimethyl-7-ethylenedioxy-2-methal1yl 1- (ii-hydroxyethyl) -1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene-4-one and 2,4b-dimethyl-7-ethylenedioxy-2-rnethallyl-l-carboxy methyl-1,2, 3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-onc yields 2,4b-dimethyl-2-methallyl-1-(fi-hydroxyethyl)-1,2, 3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrenc 4,7- dione and 2,4b-dimethyl-2-methallyl-1-carboxymethyl-1,2, 3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene 4,7- dione respectively.

EXAMPLE 2 2,4b-dimethyl 7 ethylenedioxy-Z methallyl-l-carboxymethyl 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one In another experiment carried out as described in Example 1, the combined ether extracts were extracted with aqueous sodium hydroxide solution at this point to remove the carboxymethyl compound before chromatographing the mixture. The sodium hydroxide extract was then acidified with aqueous sodium dihydrogen phosphate solution whereupon crystalline 2,4b-dimethyl-7-ethylenedioxy-2-methallyl-1 carboxymethyl-1,2,3,4,4a,4b,5,6,7,8, 10,lOa-dodccahydrophenanthrene-4-one separated from the solution.

Chromatography of the ether extracts was then carried out as described in Example 1 with the exception that the methanol elution was omitted.

EXAMPLE 3 2,4b-dimethyl-7-ethylenedioxy-Z- (fi-q-dihydroxyisobutyl) I-acetaldehydo 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrenei-one To a solution of 145 mg. of 2,4b-dimethyl-7-ethylenedioxy 2-methallyl-l-acetaldehydo 1,2,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene-t-one in 1.5 cc. of henzene and 0.5 cc. of tetrahydrofuran was added m2.

ature the precipitated osmate ester was dissolved in 6.5

cc. of ethanol and treated with a solution of 700 mg. of sodium sulfite in 4 cc. of water. The mixture was agitated thoroughly for twenty minutes to effect hydrolysis of the osmate ester. After standing briefly the upper layer was decanted and the lower layer was washed repeatedly by decantation with ethanol. The organic solutions were combined and concentrated to a small volume. Extraction with chloroform followed by washing with water, drying and concentration yielded crystalline 2,4b-dimethyl-7-e'thylenedioxy-2- (fl-y-dihydroxyisobutyl -1-acetaldehyde-l,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene-4-one, melting at 174-177" C., after purification by recrystallization from benzene.

Upon hydrolysis with acid, 2,4b-dimethyl-7-ethylene dioxy-2-(B,' -dihydroxyisobutyl)-1-acetaldehydo 1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4-one is converted to 2,4b-dimethyl-2-(,9,'y-dihydroxyisobutyl)-1- acetaldehydo l,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4,7-dione.

EXAMPLE 4 2,4b-dimethyl-7-ethylenedioxy Z-(fl-ketopropyD-I-acetaldehyde 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydraphenanthrene-4-0ne To 200 mg. of 2,4b-dimethyl-7-ethylenedioxy-2-(pm dihydroxyisobutyD-l acetaldehydo-1,2,3,4,4a,4b,5,6,7,8,

8 phenanthrene-4-one. The pure material melted at 131 133 C. after being recrystallized from ether.

Upon hydrolysis with acid, 2,4b-dimethyl-7-ethylene dioxy-2-(fl-ketopropyl)-1-acetaldehydo-1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene-4-one is converted to 2,4b-dimethyl-2-(fl-keto-propyl)-1 acetaldehydo-1,2,3,4, 4a,4b,5,6,7,9, l 0, l Oa-dodecahydrophenanthrene 4,7 -dione.

EXAMPLE 5 dl-A -3-ethylenedioxy-pregnadiene-l1,20-dione Various changes and modifications in the procedure 5 herein disclosed will occur to those skilled in the art, and to the extent that such changes and modifications are embraced by the appended claims, it is to be understood that they constitute part of our invention.

What is claimed is:

1. 2,4b-dimethyl-l-acetaldehydo 2-(p-ketopropyl)-7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one.

2. 2,4b-dimethy1-l-acetaldehydo Z-(B-ketopropyD-l, 2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4,7- dione.

No references cited. 

1. 2,4B-DIMETHYL-1-ACETALDEHYDO-2-(B-KETOPROPYL)-7ETHYLENEDIOXY - 1,2,3,4,4A,4B,5,6,7,8,10,10A - DODECAHYDROPHENANTHRENE-4-ONE. 